The use of percutaneous transluminal coronary angioplasty (PTCA) to alleviate the myocardial ischemia associated with advanced multi-vessel coronary artery disease has increased exponentially in the past decade. However, the long term efficacy of PTCA is significantly limited by the high incidence of vascular restenosis observed in as many as 40% of patients undergoing this procedure (1). The lack of an effective pharmaceutical modality to retard this process is indicative of the poor understanding of the precise molecular mechanisms underlying the pathophysiology of vascular restenosis.
The resultant neointima formation associated with balloon angioplasty is a complex process actively involving various cell types which secrete many different cytokines and growth factors seminal to the local inflammatory response (2). These cytokines include, but are not limited to, interleukin 1 (IL-1), platelet-derived growth factor (PDGF), and a number of colony stimulating factors (CSFs) and interferons (IFNs) (3,4). The major cellular component of the atherosclerotic lesion is the vascular smooth muscle cell, which, upon exposure to these soluble factors, migrates into the intimal layer and proliferates. In restenotic lesions, VSMCs express a synthetic phenotype and secrete many cytokines and matrix proteins, which further promotes VSMC growth in an autocrine fashion (5,6). It has been suggested that cytokine-induced activation of VSMC in the media resulting in intimal thickening is the most critical cellular event in the restenotic process (5-8).
Interferons, including IFN.gamma., interact with target cells to induce expression of a number of IFN-specific genes (9). IFN.gamma.-inducible genes manifest their biological activities by anti-viral, immune modulatory, and anti-proliferative effects (10). This is particularly true in VSMC, as it has been shown that proliferation of these cells is inhibited by lymphocyte factors, including IFN.gamma. (11,12). The anti-proliferative effects of IFN.gamma. on VSMC can be exerted indirectly, though generation of nitric oxide (13), or directly, though generation of the Interferon Regulatory Factor (IRF) family of transcriptional regulators, which act as activators or repressors of IFN.gamma.-inducible genes (14,15).
Transcriptional regulators encode transcription factors, which are proteins that directly link external, receptor-mediated events with gene expression. Research has been directed to identifying transcriptional regulators and transcription factors that might play a role in restenosis.
Allograft Inflammatory Factor-1 (AIF-1) is a gene which has been studied to determine what role it might play in the restenotic process. The sequences of rat and human AIF-1 are disclosed in WO 95/17506. AIF-1 is induced by serum and many cytokines.
All references cited herein are incorporated herein by reference in their entireties.